Synthesis of SGLT2 Inhibitors by Means of Fukuyama Coupling Reaction.

Disclosed herein is a novel and efficient synthesis of dapagliflozin and canagliflozin, the most advanced sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors), for the treatment of type 2 diabetes mellitus (T2DM). Per Ac-protected thioester was prepared by the treatment of per Ac d-gluconolactone with 1-dodecanethiol and iPrMgCl without affecting labile Ac-protecting groups. Aryl bromide (ArBr) was synthesized through reduction of diaryl ketone to diaryl methane by the TiCl4/NaBH4/DME-MeOH reduction system. Fukuyama coupling of the thioester with aryl zinc reagent prepared from ArBr gave a multifunctional aryl ketone at 40 °C in a high yield where the use of a limited amount of a mixed solvent (7.2 volumes (v), THF:toluene:DMF = 3v/4v/0.2v) was crucial to achieve the higher yield. After cleavage of the THP group, hydroxy ketone obtained was treated with methanesulfonic acid (MSA) in MeOH to give a methoxy-cyclized product in a single step and in a quantitative yield, which was allowed to silane reduction to furnish dapagliflozin in an excellent yield. By following the same procedure, canagliflozin was synthesized. The current synthetic method is featured by high yields, mild reaction conditions, and the use of inexpensive reagents and readily cleavable protecting groups.

A general synthetic strategy and the anti-proliferation properties on prostate cancer cell lines for natural phenylethanoid glycosides.

A general strategy for the synthesis of phenylethanoid glycosides (PhG) including echinacoside 1, acteoside 2, calceolarioside-A 3 and calceolarioside-B 4 is reported. The strategy features the application of low substrate concentration glycosylation and N-formyl morpholine modulated glycosylation methods for the construction of 1,2-trans ß- and α-glycosidic bonds. The reported strategy does not invoke the use of the participatory acyl protecting function, which is incompatible with the ester function present in target PhG compounds. A preliminary study of the anti-proliferation properties of the PhG compounds 1­4 was performed; the acteoside 2 exhibited the best inhibition on the prostatic cancer cell proliferation.

Modulating glycosylation with exogenous nucleophiles: an overview.

The major challenge in carbohydrate synthesis is stereochemical control of glycosidic bond formation. Different glycosylation methods have been developed that are based on the modulation effect of external nucleophiles. This review highlights the development, synthetic application, challenges and outlook of the modulated glycosylation methods.

New Synthesis of Diarylmethanes, Key Building Blocks for SGLT2 Inhibitors.

Synthesis of diarylmethanes, a key building block for SGLT2 inhibitors, has been developed through ketone synthesis by Friedel-Crafts acylation with TiCl4, followed by reduction with TiCl4/NaBH4. The new protocol proceeded more cleanly than the previous methods employing AlCl3 and BF3·OEt2/Et3SiH to provide the diarylmethanes corresponding to canagliflozin, empagliflozin, and luseogliflozin in a highly expedient and affordable manner. In the case of a diarylmethane for the synthesis of dapagliflozin, the reduction step took place by an alternative method using InCl3/Al/BF3·OEt2.

Neighboring-group participation by C-2 ether functions in glycosylations directed by nitrile solvents.

Ether-protecting functions at C-2 hydroxy groups have been found to play participating roles in glycosylations when the reactions are conducted in nitrile solvent mixtures. The participation mechanism is based on intramolecular interaction between the lone electron pair of the oxygen atom of the C-2 ether function and the nitrile molecule when they are positioned in a cis configuration. A 1,2-cis glycosyl oxazolinium intermediate is formed. This participation, in conjunction with the anomeric effect of the glycosyl donor, confers high 1,2-trans selectivities on glycosylations. Further application of this concept has led to efficient preparations of α-(1→5)-arabinan oligomers.

General Homologation Strategy for Synthesis of L-glycero- and D-glycero-Heptopyranoses.

A general and stereospecific homologation strategy for the synthesis of heptopyranosides is reported. The strategy employs the Wittig olefination and proline-catalyzed α-aminoxylation to achieve one carbon elongation and stereoselective hydroxylation at the C6 position, respectively. The L-glycero- and D-glycero-heptopyranosides can be obtained with nearly perfect stereoselectivity. Further study reveals the difference in the chemical shift of the C6 proton of L/D-glycero-heptopyranosyl diastereomers, which is found to be useful for assignment of the configuration of heptopyranosides.